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Inhibition of Breast Cancer Bone Metastasis by LRP5-Overexpressing Osteocytes via the LIMA1/MYO5B Signaling Axis
Yaning Chen1,2, Zicheng Wang1, Yu Sun3
1Department of Pharmacology, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China.
Abstract:
Bone metastasis in breast cancer remains a major therapeutic challenge because current osteoclast-targeted therapies do not fully disrupt the tumor-bone vicious cycle. Osteocytes, the most abundant bone cells, are increasingly recognized as key regulators of bone-tumor crosstalk. Previous work has shown that osteocyte-specific overexpression of the Wnt co-receptor LRP5 inhibits breast cancer-induced osteolysis and generates conditioned medium (CM) with tumor-suppressive activity. Proteomic analysis identified LIM domain and actin-binding protein 1 (LIMA1) as a central mediator that interacts with Myosin Vb (MYO5B), suggesting the role of the LIMA1/MYO5B regulatory axis. This study demonstrates that CM derived from LRP5-overexpressing osteocytes suppresses EO771 breast cancer cell proliferation, migration, and invasion, and downregulates tumor-promoting proteins, including MMP9, Snail, IL-6, and TGF-β1, while upregulating the apoptosis-related protein cleaved caspase-3. These effects were largely reversed by knockdown of LIMA1 or MYO5B. In syngeneic mouse models of mammary tumors and bone metastasis, systemic administration of LRP5-overexpressing osteocyte-derived CM reduced tumor burden and osteolytic bone destruction, whereas genetic knockdown of LIMA1 in osteocytes or MYO5B in tumor cells abrogated these protective effects. Collectively, these findings indicate that LRP5 activation in osteocytes engages the LIMA1/MYO5B signaling axis that inhibits breast cancer progression and osteolysis, disrupts tumor-stromal interactions, and restores bone-tumor homeostasis, thereby providing a potential therapeutic strategy to break the vicious cycle of bone metastasis in breast cancer.
Insights
Activating LRP5 in osteocytes, the most abundant bone cells, suppresses breast cancer growth and bone destruction by regulating the LIM domain and actin-binding protein 1 (LIMA1)/Myosin Vb (MYO5B) axis, offering a new therapeutic strategy for bone metastasis.
Area of Science:
- Bone Biology
- Cancer Biology
- Cell Signaling
Background:
- Bone metastasis in breast cancer is a significant challenge due to the incomplete efficacy of current therapies targeting osteoclasts.
- Osteocytes play a crucial role in regulating the crosstalk between bone and tumors.
- Previous studies indicated that osteocyte-specific LRP5 overexpression inhibits osteolysis and produces tumor-suppressive conditioned medium (CM).
Purpose of the Study:
- To investigate the therapeutic potential of LRP5 activation in osteocytes for treating breast cancer bone metastasis.
- To elucidate the molecular mechanisms underlying the tumor-suppressive effects of LRP5-overexpressing osteocyte-derived CM.
- To evaluate the in vivo efficacy of LRP5-mediated signaling in preclinical models.
Main Methods:
- Proteomic analysis to identify key mediators in LRP5-osteocyte CM.
- In vitro studies using EO771 breast cancer cells treated with CM, LIMA1/MYO5B knockdown.
- In vivo studies using syngeneic mouse models of breast cancer bone metastasis treated with CM or with genetic knockdown of LIMA1/MYO5B.
Main Results:
- LRP5-osteocyte CM suppressed breast cancer cell proliferation, migration, and invasion, downregulating MMP9, Snail, IL-6, and TGF-β1, while upregulating cleaved caspase-3.
- These effects were reversed by LIMA1 or MYO5B knockdown.
- Systemic CM administration reduced tumor burden and osteolytic bone destruction in vivo, with protective effects abrogated by LIMA1/MYO5B knockdown.
Conclusions:
- LRP5 activation in osteocytes, via the LIMA1/MYO5B axis, inhibits breast cancer progression and osteolysis.
- This pathway disrupts tumor-stromal interactions and restores bone-tumor homeostasis.
- Targeting the LRP5-LIMA1/MYO5B pathway presents a promising therapeutic strategy to combat breast cancer bone metastasis.
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